Vascular Brain Damage in Thalassemia Syndrome: An Emerging Challenge

Thalassemia syndromes are the most prevalent monogenic hemoglobinopathy in the world. In Iran, thalassemia is a public health problem because this country has been located on the thalassemia belt. In recent decades, considering that the life expectancy of patients with thalassemia has dramatically improved, some unrecognized complications have emerged in these individuals. One of these complications is a hypercoagulable state that may lead to thromboembolic events (TEE). The TEE may involve any organ in the body, including the central nervous system. Ischemic cerebrovascular events in thalassemic patients have been divided into two categories, namely overt stroke and silent cerebral infarcts (SCI). Overt stroke often develops in patients with beta-thalassemia major; however, patients with thalassemia intermedia usually suffer from SCI. This review article discusses brain vascular involvement.

In Iran, thalassemia is a public health problem because this country has been located on the thalassemia belt. The average gene frequency rate in Iran is approximately 4%. The country-wide thalassemia prevention program was started in 1997 in Iran, resulting in a significant reduction in the thalassemic newborn rate (2). The main part of treatment in β-TM and some forms of β-TI is repeated regular transfusion resulting in iron accumulation in different vital organs. Therefore, these patients need iron chelator drugs to prevent hemosiderosis in those with transfusion-dependent β-thalassemia (TDT) (3).
Magnetic resonance imaging (MRI) T2* is a highly sensitive technique for the assessment of organspecific hemosiderosis (4). In recent decades, the life expectancy of patients with TDT has dramatically improved since some unrecognized complications have emerged in these individuals.
Profound hemostatic alterations are among these morbidities which may occur in TM and especially TI patients (5). Multiple factors have been responsible for a hypercoagulable state in these patients (6)(7)(8). These thromboembolic events (TEE) may occur both in splenectomized and non-splenectomized patients (9). The TEE may involve various organs in the body, including deep vein thrombosis (DVT), portal vein thrombosis, pulmonary embolism, and even arterial occlusion (10,11). Furthermore, brain vascular involvement and cerebral micro-thrombosis are other complications that may occur in TDT and nontransfusion-dependent thalassemia (NTDT) (12).

β-Thalassemia
Multiple abnormalities in platelets, red blood cells (RBC), coagulation factors, and physiologic anticoagulants, including protein C, protein S, and antithrombin III (ATIII), are responsible for the pathogenesis of a hypercoagulable state in thalassemia syndromes (13). As previously mentioned, TEE are more common in NTDT in comparison to those in well-transfused TDT. In a large epidemiological study performed on 8860 patients in the Mediterranean area and Iran, TEE were observed to be 4.38 times more prevalent in β-TI, compared to those in β-TM (14). In addition, splenectomized patients with NTDT are more vulnerable to episodes of thromboembolism (15).
In NTDT patients who were splenectomized, a nucleated RBC count of > 300 × 10 6 /L, platelet of > 500 × 10 6 /L, and RBC transfusion naivety have been correlated with the increased incidence of TEE (16). Independent risk factors for the development of TEE in thalassemia syndromes include splenectomy, a serum ferritin level of > 1000 ng/ ml, a hemoglobin level of < 9 gr/dl, and age of > 35 years (15). In patients with β-TM, the expression of P-selectin and CD63 have been increased.
These two markers are the indicators of in vivo platelet activation resulting in increased platelet Moreover, in patients with thalassemia, the levels of endothelial adhesion proteins (e.g., E-selection), intercellular adhesion molecule-1, von Willebrand factor, and vascular cell adhesion molecule-1 have been enhanced (13). One of the most important contributing factors in the pathogenesis of TEE in thalassemia syndromes is the reduction of protein C, protein S, and ATIII, all of which are natural physiologic anticoagulants (13,(19)(20)(21).
In thalassemic patients, due to multiple reasons, such as hepatic hemosiderosis and viral infections, varying degrees of liver dysfunction occur, and proteins C and S are very sensitive even to mild hepatic dysfunction (22).
In addition, in thalassemic patients, prothrombin fragment 1.2, which is a marker of thrombin generation, has an important role (23). Furthermore, splenectomy results in thrombocytosis, enhanced platelet aggregation, and an increased number of damaged RBC. All the aforementioned parameters could increase the risk of thromboembolism (18).

Nervous System
In patients with β-TM and β-TI, both arterial and venous TEE could be detected (14). Regarding the OPTIMAL CARE study, thromboembolic disorders (often venous thrombosis) were the fifth most prevalent morbidity among thalassemic patients occurring in almost 14% of patients (24).
Recently, there has been a report on an increasing number of cerebrovascular episodes, such as overt stroke and silent cerebral infarcts (SCI), in patients with thalassemia and sickle cell anemia (25).

Incidence of Brain Lesions
Brain vascular involvement occurs in 29-83% of TI patients; however, the rate of asymptomatic brain lesions in healthy individuals is within the range of 0-11%; therefore, these lesions are more likely to be pathological rather than regular (26,27). In different studies, there is a wide range of TEE in patients with thalassemia (both TM and TI populations), within the ranges of 0.9-4% and 3.9-29%, respectively (25). Ischemic cerebrovascular events in thalassemic patients have been divided into two categories, namely overt stroke and SCI. In SCI, the patients are often asymptomatic, and the detection of lesions without brain imaging methods is not possible (28).
In patients with β-TM, often overt stroke develops; however, patients with β-TI usually suffer from silent stroke (25).
The presence of SCI on brain imaging can be related to an increased risk of subsequent overt stroke, a transient ischemic attack, and a marked reduction in cognitive function, both in children and adults (29). Moreover, in case of asymptomatic brain lesions in thalassemic patients, some authorities alter the therapeutic modalities; therefore, the early detection of these lesions has clinical importance (30). On the other hand, these asymptomatic brain lesions may cause permanent neurological deficits

Characteristic of Central Nervous System Lesions
In patients with β-TI, SCI have been diffusely

Biomarkers of Brain Ischemia
Neuron-specific enolase (NSE) and S100 calciumbinding protein β (S100β) are two biomarkers that can be used for the identification of brain ischemia and CNS injury (40

Treatment
Stroke is the third leading cause of mortality (41).
Cerebral TEE, both overt and silent, have been high-risk groups (41). The cut-off value of platelet count for the beginning of aspirin therapy (>500 × 10 9 /L versus >800-1000 × 10 9 /L) is controversial requiring further evaluation in future studies (35).

Blood Transfusion
The mechanism of regular blood transfusion in the prevention and treatment of TEE in thalassemia patients is the reduction of phosphatidylserine exposure on the surface of RBC (43). Regular blood transfusions are recommended for patients with symptomatic CNS thrombosis (44).

Direct Oral Anticoagulants
Direct oral anticoagulants (DOACs) with direct inhibition of factor IIa (dabigatran) or Xa (rivaroxaban and apixaban) have been used for stroke prevention in atrial fibrillation (45). These

In Conclusion
In recent years, the survival of patients with TDT has dramatically improved since brain vascular abnormalities, such as overt and silent stroke, have been emerged in these individuals. It seems that cerebral infarction and vascular injury begin in late childhood. In these patients, diagnostic MRI can be helpful to monitor early asymptomatic or subclinical vascular damage in the brain, especially when they reach the second decade of life. However, high-risk patients with thrombocytosis (a platelet count of >500,000 mm 3 ), splenectomy, and severe iron overload should be under strict follow-up, be evaluated on a regular periodic basis, and undergo brain MRI at least once every 3 years.
The emphasis on effective iron chelation, the addition of low-dose aspirin for the prevention of thromboembolic sequelae in high-risk thalassemia patients, and the inclusion of brain MRI in routine periodical evaluation are all advised for thalassemia patients to treat the individuals with asymptomatic brain damage as soon as possible.